Transcript Breast Cancer Risk Assessment and Prevention Strategies

Breast Cancer Risk Assessment &
Prevention Strategies
Generosa Grana, MD
Professor, Cooper Medical School of Rowan University
Director, MD Anderson Cancer Center at Cooper
Overview
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Factors that affect breast cancer risk
Tools to assess risk
Role of genetics in this process
Prevention and Screening
Assessing Risk of Cancer
Factors to Assess:
Family history
• Type of cancers, age, bilaterality…
Reproductive factors
• Age menarche, menopause, first live birth
Personal health history
• biopsy, obesity, etc.
Utility of Risk Assessment
Benefits of Risk Assessment:
• To individualize risk
• To make decisions about:
– Genetic testing
– Screening (age to initiate, screening interval, screening
modalities, diseases to screen for)
– Chemoprevention
– Prophylactic surgery
• To plan lifestyle / dietary / or other interventions - HRT
How to assess
• Models available
• Role of genetic testing
Risk Models - Considerations
– What information can the risk model give you?
• Breast cancer – risk (lifetime, 10 year, 5 year)
• Gene mutation – prior probability
– Is the model validated and in what populations?
– What are the benefits of a particular model?
– What are the limitations of a particular model?
Risk Models
Breast Cancer Risk
Breast Cancer Risk &
BRCA Mutation
• Gail
• IBIS/Tyrer-Cuzick
• Claus
• BRCAPRO
– Not validated, outdated (data
collected before BRCA
testing)
– No personal risk factors
(except oophorectomy), no
3rd degree relatives
• BOADICEA
– No personal risk factors,
cumbersome data entry
Gail Model
• Used to determine lifetime
and 5 year risk of breast
cancer
– Lifetime: MRI if >20%
– 5 year risk:
chemoprevention if >
1.67%
• Cannot be used;
– if patient has had breast
cancer or LCIS
– Patient is mutation positive
– <35 years old
• Fails to capture: paternal
history, age of cancers,
ovarian or other cancers
IBIS (Tyrer-Cuzick)
International Breast Cancer Intervention Study
IBIS (Tyrer-Cuzick)
International Breast Cancer Intervention Study
• Validated in European population
• Used to determine lifetime and 10 year risk of breast
cancer
– Lifetime: MRI
– 10 year: not intended for determination of
chemoprevention suitability
• Can be used if:
– patient has had LCIS
– patient is mutation positive
• Tends to overestimate risk if there is a history of
benign breast disease such as hyperplasia or if a
woman has a history of LCIS
Usefulness of Risk Information Vs. Usefulness of
Genetic Information
Both
Imaging recommendations
Lifestyle change
Drug therapy
Prophylactic surgery
Risk Information
Individual only
Numerical value
Genetic Information
Individual & Family
More precise assessment
BRCA1-2 Mutations Increase the Risk of Cancer More Than
Other Factors
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Relative
risk of
breast
cancer
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BRCA1-2
mutation
Early
menarch
Late age
at birth of
1st child
Benign Hormone
Alcohol
breast replacement
use
disease
therapy
Family
history
Evolving face of Gene Testing
HEREDITARY BREAST CANCER GENES
HIGH RISK
MODERATE RISK
INCREASED RISK
BRCA1
ATM
BARD1
BRCA2
CHEK2
BRIP1
CDH1
PALB2
NBN
PTEN
RAD50
STK11
RAD51C
TP53
RAD51D
many others…
Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
**possible increased risk of breast cancer for carriers**
Risk Associated with BRCA1/2
• Breast Cancer
By age 40
By age 50
By age 70
Population risk
.5%
2%
7%
Carrier risk
10-20%
33-50%
56-87%
• Ovarian Cancer
1%
44% BRCA1
27% BRCA2
Ford. Lancet 1994;343:692-695
Struewing. NEJM 1997;336:1401-1408
Easton. AJHG 1995;56:265-271
Risks of Other Cancers
Male breast cancer (primarily BRCA2)
• < 6% by age 70
Prostate (BRCA2, possibly BRCA1)
• 20% by age 80; 3- to 7-fold increase RR
Pancreatic cancer (BRCA2) (Rare BRCA1)
• 2-3% by age 80; 3- to 4-fold increase RR
Colon
• Little or no increased risk
Melanoma (BRCA2)
Am J Hum Genet 1997;61: 120-8
JNCI 1999;15:1310-6
Dis Colon Rectum 1999;42:1041-5
Risk associated with other genes
Hereditary Diffuse Gastric Cancer Syndrome
• CDH1 gene
• Diffuse gastric cancer – 67-83% risk
• Lobular cancer of the breast -39-52% risk
Peutz-Jeghers Syndrome
• STK11/LKB1 gene
• Breast cancer- 44-50%
• Ovarian cancer – 18-21% risk (ovarian sex cord tumors the most common)
Lynch Syndrome
• Mismatch repair genes (MMR)- MLH1, MSH2, MSH6, PMS2
• Ovarian cancer –4-24% risk (4-24% with MLH1 and MSH2, 1-11% for MSH6)
• Breast cancer risk – conflicting data
• Uterine cancer risk -25-60% MLH1 and MSH2; 15-26% MSH6 and PMS2)
NCCN version 2.2016 “Genetic/Familial High Risk Assessment: Breast and Ovarian”;
www.nccn.org
Beyond Brca1/2
• Understanding of role played by these genes in
cancer development
– Brca1 /2 alterations also play a role in non-hereditary
forms of Breast cancer
• Understanding of interaction of these genes with
other pathways in the cancer cell – RAD etc.
• Identification of Drugs that may target these
cancers – PARP inhibitors, platinum compounds
Patient vs. Family Issues
• Patient
– Impact on Risk, Prevention & Treatment
• Family
– Impact on risk & prevention
• Societal
– Societal Screening ??
Features of Hereditary B/O Cancer
Breast
• BRCA1: more likely to be ER/PR (-)
• BRCA2: more likely to be ER/PR (+)
• Prognosis appears to be the same as
for sporadic breast cancer of same
histology
Ovary
• Predominantly papillary serous
• Prognosis may be better than for
sporadic ovarian cancer
Lancet 1998;351:316-21
J Clin Oncol 1999;17:3396-402
New Engl J Med 1996;335:1413-6
JAMA 2000;283:2260-5
Clinical Management of
BRCA Mutation-Positive Patient
Positive BRCA1 or BRCA2
test result
Possible testing for
other adult relatives
(FDR at 50% risk)
Increased
surveillance
Prevention
Prophylactic Lifestyle
surgery
changes
ASCO
Increased Surveillance - Breast
Recommendations for women:
• Breast awareness starting at age 18
• Clinical breast exam every 6-12 months starting at age 25 (no clinical trials
done)
• Breast screening:
– Age 25-29 – annual breast MRI preferred or mammogram if MRI not
available (individualize if breast cancer diagnosed in family < 25)
– Age 30-75-annual mammogram + MRI
– Age >75- management on individual basis
•
Ongoing research looking at various imaging modalities and schedule (Lowry et al. Cancer 2012)
Recommendations for Men
•
•
Breast self exam training and education starting age 35
Clinical breast exam yearly starting age 35
NCCN version 2.2016 “Genetic/Familial High Risk Assessment: Breast and Ovarian”;
www.nccn.org
Increased surveillance - Ovary
• For those not selecting salpingooophorectomy:
• Can do transvaginal US and Ca-125 – but data
do not support routine ovarian screening and
these two tests have not been shown to be
sufficiently sensitive or specific to support a
recommendation.
NCCN version 2.2016 “Genetic/Familial High Risk Assessment: Breast and Ovarian”;
www.nccn.org
Surveillance- other
• Education regarding signs and symptoms of
cancers associated with mutations.
• No specific guidelines for screening for
pancreas or melanoma – but may be
individualized
• Ongoing research looking at screening for
pancreas cancer – endoscopic US…
Chemoprevention
• Tamoxifen & Evista – ~ 50 % reduction in high risk
women – data in mutation carriers very limited
• Aromatase Inhibitors - ~50% reduction in high
risk women
• OCP – reduce risk of ovarian cancer by ~50% in
Brca1 and ~60% in Brca2
– OCP conflicting data on breast cancer risk
– Increased risk in Brca1 but not in Brca2
Narod et al NEJM 1998
Moorman et al JCO 2013
Haile et al Cancer Epid Bio & Preven 2006
Selection of Drug Therapy
Factors to consider
Menopausal status
– tamoxifen in pre & post; AI and Evista in post only
Other health issues:
– Bone health, prior ho TE events
– Severity of vasomotor symptoms,
Toxicity
– Tamoxifen -increased risk endometrial cancer,
cataracts, TE events; + effect bone
– Evista- increased TE events; + effect bone
– AI – arthralgias, negative effect on bone
Prophylactic Surgery
Mastectomies
Prophylactic mastectomies
• Decrease risk of breast cancer by ~ 90%
• Psychosocial effects of surgery
• Type and timing of reconstruction
Hartman et al. NEJM 1999
Hartman et al NEJM 2001
Meijers-Heijboer et al. NEJM 2001
Rebbeck et al JCO 2004
Prophylactic surgery - ovaries
Bilateral salpingo-oophorectomy
Recommended for women between 35-40 and upon completion of
child bearing.
• Reduced risk of ovary, fallopian or primary peritoneal cancer - 80-85%
• Reduced all cause mortality by 77% - among all ages in Brca1 but only in
ages 41-60 in Brca2 (
• Detection of clinically occult neoplasm at time of RRSO – 4.6% in Brca1
and 3.6% in Brca2
• RRSO reduces risk of breast cancer by ~50%
• Greater protective effect for women undergoing surgery <40 vs. 41-50.
nonsignificant reduction in women >51
• Impact on & management of menopausal symptoms
Rebbeck et al NEJM 2004
Rebbeck et al JCO 2005
Chlebowski et al
Salpingectomy vs. Oophorectomy
SGO Clinical Practice Statement: Salpingectomy for
Ovarian Cancer Prevention
• November 2013
• “Salpingectomy may be appropriate and feasible
as a strategy for ovarian cancer risk reduction”
•
women who have BRCA1 or BRCA2 germline mutations should be counseled
regarding bilateral salpingo-oophorectomy, after completion of childbearing, as
the best strategy for reducing their risk of developing ovarian cancer. In the event
that these women opt to delay or forego risk-reducing bilateral salpingooophorectomy, they should be counseled regarding risk-reducing salpingectomy
when childbearing is complete followed by oophorectomy in the future, although
the safety of this approach has not been studied
Lifestyle modification
Much research ongoing looking at each of these
areas. Data exists in general population and in
breast cancer survivors but no data on mutation
carriers
• Exercise
• Alcohol consumption
• Dietary strategies
Thank you!
questions / comments?